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Transcutaneous Electrical Tragus Nerve Stimulation to Reduce Inflammation in Acute Decompensated Heart Failure (NCT02898181)

Acute Decompensated Heart Failure (ADHF) is a major cause of morbidity and mortality. It is associated with increased systemic inflammation. Previous studies have demonstrated increased levels of cytokines such as C-reactive protein (CRP), interleukin-1 (IL-1), interleukin-6 (IL-6), interleukin-10 (IL-10) and Tumor Necrosis Factor alpha (TNFα) in patients with heart failure (HF). Increased activity of sympathetic nervous system in ADHF is linked to inflammation. Previous anti-inflammatory drug therapies in HF have demonstrated no significant impact on cardiovascular outcomes. Low-level vagus nerve stimulation (LLVNS) is a non-invasive way to modulate autonomic tone and thereby inflammation. Vagal nerve stimulation is thought to increase the parasympathetic activity and suppress the sympathetic activity. Clinical studies of vagal stimulation in chronic HF have been negative. Recent experimental and clinical data suggest that low level tragus nerve stimulation (LLTNS) may produce the same desired neuromodulator effect compared to LLVNS. It is however unknown if LLTNS in ADHF will directly lead to a reduction in the levels of pro-inflammatory cytokines (CRP, IL-1, IL-6 and TNF-α) and an increase in the level of anti-inflammatory marker IL-10.The objective of this proposal is to determine the impact of LLTS on inflammatory cytokines in patients with ADHF. Patients will be randomized to either active or no stimulation(~8 hours daily). Serum collected will (post admission and on days 2, 3 and 4 post admission) will be used for cytokine measurement. This investigation will likely establish the first evidence of effects of LLTS on suppression of inflammation in patients presenting with ADHF.
  • Device: Tragus nerve stimulation
    Active LLTS will be performed by use of a transcutaneous electrical nerve stimulation (TENS) device with electrodes attached to the tragus of the ear.TENS will be applied continuously for 8 hours daily (4 hours twice daily)
    Ages eligible for Study
    18 Years to 75 Years
    Genders eligible for Study
    Accepts Healthy Volunteers
    Inclusion Criteria:
    • Patients admitted with ADHF will undergo echocardiography which is considered standard of care. If estimated LVEF is 40% patients will be enrolled in the study.
    Exclusion Criteria:
    • Significant valvular disorder (i.e., prosthetic valve or hemodynamically relevant valvular diseases such as severe aortic or mitral stenosis, severe aortic or mitral regurgitation)
    • Complex congenital heart disease (Tetralogy of Fallot patients, single ventricle physiology)
    • Recurrent vaso-vagal syncopal episodes
    • Unilateral or bilateral vagotomy
    • Sick sinus syndrome
    • 2nd or 3rd degree AV block
    • bifascicular block or prolonged 1st degree AV block (PR>300ms)
    • Pregnant patients
    • Prisoners
    • Advanced renal dysfunction(defined as eGFR < 30, stage 4 or 5 chronic kidney disease)
    A. Specific aims

    1. To examine the effect of intermittent (~8 hours daily) LLTS on inflammatory cytokines (CRP, IL-1, IL-6, IL-10 and TNFα) in patients presenting with Acute Decompensated Heart Failure relative to control group.

    2. Patients will be randomized to either active LLTS or control group.

    3. LLTS will be delivered through a transcutaneous electrical nerve stimulation (TENS) device for ~8 hours daily over the course of the hospital stay.

    4. Change in the levels of inflammatory cytokines will be compared between the two groups at the pre-specified time points, using repeated measures ANOVA. These cytokines will be measured using multiplex immunoassays. Gene expression of these inflammatory cytokines will be measured from peripheral blood monocytes, using commercially available microarrays.

    B. Background and significance Heart Failure (HF) is a major cause of morbidity and mortality in United States. It is estimated that approximately 5.1 million Americans suffer from Heart Failure and the number of annular discharges with heart failure exceed 1 million. Although the survival has significantly improved for patients with heart failure the absolute mortality date for heart failure remains approximately 50% within 5 years of diagnosis.While several clinically proven treatment strategies exist for patients with chronic heart failure very limited data exists in patients presenting with ADHF. The quest for newer therapies continues.

    Although a clear link has been established between inflammation and heart failure, therapies targeting the inflammatory cascade have been disappointing. Randomized clinical trials targeting cytokines using a wide array of drug therapies have failed to demonstrate a meaningful reduction in cardiovascular outcomes. None of these trial enrolled patients with ADHF and variation in inflammatory cytokines levels were not uniformly reported across these studies. Inflammation plays a central role in heart failure. The most important cytokines implicated in the progression of heart failure are CRP, tumor necrosis factor-alpha (TNF-α), interleukin (IL) 1, and IL-6 and IL-10. TNF-α is elevated in HF patients with reduced ejection fraction (EF). Increased concentrations of IL-6 have been shown in the circulation of ADHF patients. IL-1 along with TNF-α are generally thought of as prototypical pro-inflammatory cytokines. IL-1 has been demonstrated in the myocardium of patients with idiopathic dilated cardiomyopathy. IL-10 is one of the most important anti-inflammatory cytokines. It is known to down regulate the production of TNF-α, IL-1, and IL-6, respectively. In a study by Kaneko et.al, CRP values in 188 patients with idiopathic dilated cardiomyopathy were assessed. All patients had an impaired ejection fraction of less than 40%. Those patients who died during a follow up period of five years had significantly higher CRP concentrations than those who survived.

    Vagal stimulation (VS) appears to be the most direct and effective way to increase vagal tone. To date, 2 clinical studies of VS in humans have been negative. It has been previously demonstrated that a similar level of VS can be achieved non-invasively by stimulating the auricular branch of the vagus nerve via LLTNS. Low level Tragus stimulation mimics the effects of direct vagal nerve stimulation. Our group has demonstrated that LLTNS can significantly reduce inflammatory cytokines in patients with AF undergoing radiofrequency catheter ablation.

    To our knowledge there is no data that suggests that modulating the autonomic nervous system via LLTNS (by increasing the parasympathetic tone and reducing the sympathetic nervous system activity) would lead to a reduction in the circulating pro-inflammatory cytokines in patients admitted with ADHF. Since this concept has not been tested previously we have embarked on the idea of using autonomic modulation via LLTNS to reduce the level of systemic inflammation that is rampant in patients admitted with ADHF. We hypothesize that LLTNS will lead to a reduction in the levels of pro-inflammatory cytokines (such as TNF-α, IL-1, IL-6, CRP) and reduced anti-inflammatory cytokine IL-10, in patients admitted ADHF.

    C. Preliminary studies The investigators intend to perform the first in human pilot study to determine the impact of LLTNS on inflammatory cytokines in patients presenting with ADHF.

    D. Research design and Methods This is a prospective, randomized, and controlled pilot study. Patients presenting with ADHF to OU Medical Center will be eligible for inclusion in the study.

    Definition of ADHF: Acute Decompensated Heart Failure (ADHF) can be defined as the sudden or gradual onset of the signs or symptoms of heart failure requiring unplanned office visit or emergency room visit leading to hospitalization. Regardless of the underlying precipitant of the exacerbation, pulmonary and systemic congestion due to increased left- and right-heart filling pressures is a nearly universal finding in ADHF.

    Patients will be recruited from the inpatient services of the University of Oklahoma Health Sciences Center. Study coordinator will screen all patients and if they meet the inclusion criteria they will be enrolled. Informed consent will be obtained prior to enrollment in the study. The randomization schedule will be implemented with the use of a central computerized system. Blocked randomization will be used to decrease the chance of imbalances in the two groups over time.

    After informed consent and screening procedures are completed, all patients will undergo a baseline blood draw for inflammatory markers. Patients will then be randomly assigned (1:1) to active or control group. The clinical coordinator will instruct the patients on the proper use of the device. These study personnel will be designated to address the patients' questions and concerns as well as to record any side effects related to the use of the device.

    Active LLTS will be performed by use of a transcutaneous electrical nerve stimulation (TENS) device with electrodes attached to the tragus of the ear, which is innervated by auricular branch of the vagus nerve. In the active group, the ear clip electrode will be attached to tragus in the active stimulation group. TENS will be applied continuously for 8 hours daily (4 hours twice daily) The clinical coordinator will instruct the patients on the proper use of the device. In patients with pacemakers, the pacemaker will be tested with the TENS unit to assess for interaction. In case of interaction (the stimulation artifact of the TENS unit picked up by the pacemaker), the patients will be excluded from the study.

    The choice of treatment for ADHF will be left at the discretion of the treating physician. The experimental device will be used in addition to all the other medications; in other words, the device will be used only with individuals continuing treatment for ADHF.

    Patients will be enrolled in the study over 12 months (total duration of the study). During the baseline hospital admission a complete history and physical examination will be done by one of the investigators. Laboratory data, electrocardiographic data and echocardiographic data will also be reviewed. 20ml of blood will be drawn for cytokine analysis.

    Investigators intend to recruit 80 patients. Blood samples (20ml) will be collected at baseline and daily AM (on days 2,3 and 4) throughout the hospital stay. Samples will be centrifuged within 30 minutes of collection (2000 rcf for 10 min), and serum will be stored in aliquots at -80°C until assayed. Patients' serum will be saved frozen and processed in batches of 6 to 8. The investigators performing the cytokine assays will be blinded to group assignment. All assays will be run at the Lab at OUHSC. Inflammatory cytokines, including TNF-α, CRP and IL-1, IL-6, IL-10 will be measured using commercially available immunoassays analyzed on a flow cytometer (multiplex assays). In addition, peripheral blood mononuclear cells (PBMCs) will be isolated using MACS magnetic bead purification. Inflammatory cytokine gene expression profile will be measured at the above time points, using commercially available microarrays. Finally, investigators will determine cytokine responses to LLTS and identify predictors of response based on baseline cytokine levels. It is known that vagus nerve stimulation attenuates inflammation through the cholinergic anti-inflammatory pathway. If this pathway is important in ADHF, investigators expect a decrease in cytokines with LLTNS.

    Duration of participation: Enrolled patients will participate in this study during the index hospital admission.

    Patient enrollment: A maximum of 80 patients meeting the inclusion criteria and not meeting the exclusion criteria will be enrolled in the study. The enrollment period is expected to last for at least 12 months, given that on average 15 patients with ADHF are seen in our hospital each month and assuming that 1 out of 3 eligible patients would agree to participate in the study.

    E. Statistical methods The primary outcome of this study is the percent reduction on inflammatory cytokines during the hospital stay. Markers of inflammation will be compared between groups using repeated measures ANOVA, with 4 time points (baseline, day 1 post admission, day 2 post admission and discharge day) and 3 terms included in the model (group effect, time effect, group by time interaction). Significant interactions will be followed by time trend analyses stratified by intervention group. For all pair-wise testing, we will adjust for multiple comparisons using Tukey's method. Analyses will be based on the intention-to-treat principle. Statistical significance will be declared at 5%.

    Sample size and power calculations:

    This is the first in human study testing the concept of LLTNS in ADHF. Since this a pilot study an accurate sample size size calculation cannot be performed.

    F. Gender/Minority/Pediatric Inclusion for Research Participants will be age 18 or older. Race, minority status and gender will not affect enrollment.

    1 locations

    United States (1)
    • OUHSC
      OKC, Oklahoma, United States, 73104
    31 August, 2016
    11 April, 2017
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